The invention relates to new dermocosmetic and pharmaceutical compositions which are useful for improving and treating hyperreactive skin conditions and more generally allergic-type reactions and/or intolerance phenomena, whether they are caused by external factors or factors intrinsic to the individual.
Increasing numbers of children and adults are in fact exhibiting skin described as xe2x80x9csensitivexe2x80x9d. During a recent study in France, 70% of the women questioned stated that they had sensitive facial skin. The notion of sensitive skin covers an array of outward signs comprising reactive skin and intolerant skin. Atopic skin can also be included therein. These skin types are sometimes incorrectly known as xe2x80x9callergic xe2x80x9d by the subjects; however, while an allergic component can sometimes be evoked in the symptoms of sensitive skin, it may not be restricted to it. The triggering factors can be environmental attacks such as wind, pollution, temperature variations, excessively hard water or ill-suited hygiene, cosmetic or care products; these phenomena can also be associated with stress or emotions felt by the subject, some diets or the taking of medicaments. In addition, there exists individual predisposing factors (in particular neurological or hormonal) or familial predisposing factors which amplify these reactions.
Generally, the subject feels cutaneous discomfort which can manifest itself by subjective and/or objective signs. The skin readily gives off stabbing pains, itches or smarts and the subject may experience feelings of warmth, pricking or burning on the skin. The skin can redden or desquamate. Xerosis, seborrhoeic dermatitis, telangiectasias, vesicles or even oedema is observed, on an irregular basis.
In the most serious cases, dermatological complaints of immunoallergic type, such as atopy, eczema or neurodermatitides, may be observed.
This condition can manifest itself on the skin, the mucous membranes or the scalp. In the latter case, it may be associated with a dandruff condition and/or alopecia.
Until now, attempts have been made to prevent the appearance of these reactions by limiting the presence, in dermocosmetological formulations, of components known to be allergizing. However, it would be desirable to be able to have available truly active compositions which are capable of preventing or of relieving these symptoms by decreasing the reactivity of the skin and by improving its resistance to the triggering factors.
The Applicant Company has now found, unexpectedly, that these aims could be achieved by the use of a composition containing a synergic combination producing an active hypoallergenic complex.
Such a complex will, in addition, improve the receptivity of the skin towards other active principles.
For this reason, the subject of the present invention is a dermocosmetic composition, characterized in that it contains an immunomodulatory or hypoallergenic synergic combination of at least two components, each of these components exhibiting at least one of the following activities:
a) anti-radical
b) anti-inflammatory
c) anti-allergic,
the said components being chosen so that at least two activities a), b) or c) are present in the composition.
The subject of the invention is more particularly the use of at least two compounds chosen from components having an a) anti-radical, b) anti-inflammatory and c) anti-allergic activity for the preparation of a composition, in particular an immunomodulatory composition, exhibiting at least two of the a), b) and c) activities intended for the treatment of sensitive and/or allergic skin; according to one of its aspects, the a), b) and c) activities are exerted in the composition.
Indeed, the Applicant Company has been able to show that the combination of active principles having complementary anti-allergic, anti-radical and/or anti-inflammatory activities made it possible to effectively combat the phenomena associated with the appearance of the symptoms of sensitive and/or intolerant skin or of immunoallergic complaints, preferably via a synergy of the activities of the components.
The components forming part of the formulations according to the invention can be purified or unpurified molecules, synthetic or extracted products, mixtures of active principles or extracts which have been subjected to one or a number of fractionation stages from a starting material of plant or animal origin.
Preferably, if two components present in the formulation show an activity of the same type, it will be exerted by the involvement of a different mechanism.
As regards the anti-inflammatory activity, it can in particular be provided by prostaglandin inhibitors (cyclooxygenase route), inhibitors of cytokine production and inhibitors of the production of leukotrienes (LTB, for example, lipoxygenase route).
The component or components with anti-inflammatory activity advantageously exhibit an inhibiting activity on the production of IL-1, IL-2, IL-4, IL-5, IL-12 and/or TNF-xcex1 (Tumour Necrosis Factor).
The anti-inflammatory function can also have the consequence of decreasing the production of reactive nitro derivatives by the cells, limiting the generation of free radicals.
However, anti-radical activity is understood to mean components which are preferably chosen from free-radical scavengers, anti-lipoperoxidants and stimulants of the endogenous production of the enzymes which degrade free radicals.
Free radicals, by definition, are neutral or charged chemical species which have an unpaired electron. This xe2x80x9csingle electronxe2x80x9d endows them with specific chemical properties and a short lifetime. They are reaction intermediates which will be stabilized by combination or transfer and can be the source of a chain reaction. Mention may be made, among free radicals, of the superoxide anion O2the hydroxyl radical OH , NO or peroxides.
Enzymes which are active in endogenous defense systems against free radicals are, for example, SOD (or superoxide dismutase), catalase or glutathione peroxidase; attempts will be made to stimulate the production of these enzymes or they can be introduced exogenously.
The components providing the anti-allergic function in the composition according to the invention are preferably chosen from inhibitors of lymphocyte proliferation, inhibitors of the internalization of the molecules of the major histocompatibility complex (HLA-DR, for example) or inhibitors of cytokine production. They are advantageously capable of decreasing the production of the mediators of the inflammation which occurs during allergic phenomena.
As indicated above, the composition will exhibit at least two of the anti-radical, anti-inflammatory and anti-allergic activities. In addition, the components of the active hypoallergenic complex will be chosen so that a synergy is exerted via different mechanisms at the basis of the same activity.
Each component will preferably contribute, via a number of parameters, to the overall activity of the composition according to the invention.
The composition according to the invention advantageously has a marked inhibiting activity on the synthesis and/or the expression of neuromediators, in particular with respect to cutaneous cells, resulting from a synergy of the activities of its different components. The neuromediators can be chosen from the group comprising neurokinines A (NKA) and B (NKB), vasoactive intestinal polypeptide (VIP), calcitonin gene related peptide (CGRP), neuropeptide Y (NPY), neurotensin (NT), somatostatin (SOM), gastrin releasing peptide (GRP), nerve growth factor (NGF), PGP 9.5 (Protein Gene Product 9.5) and bombesin.
Components making possible the preparation of dermocosmetic compositions according to the invention can advantageously be chosen from the following group: Ginkgo biloba and its extracts, iramine, D-panthenol, xcex2-sitosterol, modulene, xcex1-tocopherol and its derivatives, xcex2-glucan and its derivatives, eicosapentanoic acid, 18xcex2-glycyrrhetinic acid, glycyrrhetinic acid monoglucuronide, stearyl glycyrrhetinate, Scutellaria extract, lactoferrin, green tea and its extracts, vitamin C, glutathione, epidermal thymus factor, azole derivatives and lipacid.
However, the combination of vitamin E with a Scutellaria extract is not included within the compositions according to the invention.
According to one of the aspects of the invention, the composition contains at least one component, preferably at least two components, chosen from the above group.
The azole derivatives used according to the invention can be chosen from imidazole or triazole derivatives and in particular from the group composed of: bifonazole, butoconazole, chlordantoin, chlormidazoie, cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, fluconazole, itraconazole, saperconazole, terconazole or elubiol.
This is because it has now been possible to demonstrate that these compounds exhibit in particular an anti-radical activity.
Mention may more particularly be made, among xcex1-tocopherol derivatives which can be used, of xcex1-tocopherol phosphate.
Mention may be made, among xcex2-glucan derivatives, of carboxymethyl-xcex2-glucan and drieline.
Drieline is a poly-xcex2(1xe2x86x923)-glucopyranose of formula 
with n=1000.
The molecule can be provided in the form of a 0.1% solution in water and sorbitol or in the powder form.
In one of the preferred embodiments of the invention, the composition contains a synergic combination of a Ginkgo biloba extract and of a xcex2-glucan compound.
Indeed, the Applicant Company has found that the combination of these two components made it possible to obtain the optimum combination of the functional characteristics providing the activity of the compositions according to the invention.
The glucan is composed of a xcex2(1xe2x86x923) glucose chain which can in particular be extracted from the wall of yeast cells. It is possible to subject it to chemical modifications in order in particular to improve its solubility.
The xcex2-glucan is advantageously substituted by carboxymethyl groups; it can exist in the salt form, in particular the sodium salt form. Good results are obtained with a derivative in wich the degree of substitution by carboxymethyl groups is within the range from 0.65 to 0.85 and which exhibits a pH from 5.5 to 8.5.
Ginkgo biloba is a dioecious tree from the Far East, the leaves of which are used for certain medicinal properties. They contain constituents, such as aliphatic hydrocarbons and alcohols, polyphenols, such as luteolin or quercetol, or biflavones derived from amentaflavone, and more specific constituents: ginkgolic acid, and anacardic derivatives, terpenes derived from limonene or terpenes containing a tert-butyl group.
Ginkgo extracts have been proposed for improving the symptoms of mental deficiency in the elderly, of intermittent claudicatior, of obliterating chronic arteriopathies and of Raynaud""s disease, or in the case of retinal deficiency.
They have been used in cosmetology for their protective effect with respect to free radicals.
The Applicant Company has found, unexpectedly, that ginkgo extracts have an excellent anti-inflammatory and anti-allergic activity which can be demonstrated on cutaneous cells, such as keratinocytes and macrophages. In addition, the Applicant Company has shown that this activity is potentiated in the presence of xcex2-glucan.
Extracts which are particularly suitable for the implementation of the invention are obtained from Ginkgo biloba leaves which have been subjected to a stage during which the terpene concentration has been brought to a value of less than approximately 7% and preferably of less than approximately 3% (w/w of dry extract). In one of the embodiments, this terpene concentration is less than approximately 1% w/w.
The concentration of flavone heterosides in the dry extract is advantageously greater than 24% and preferably greater than approximately 28% w/w.
The anti-inflammatory and anti-allergic properties can be demonstrated in particular with respect to in vitro models, for which a correlation exists with animal models and clinical studies already carried out on man.
It is possible in particular to operate on keratinocytes and macrophage cells because these are cells which are essential for the development of a local inflammatory reaction. Moreover, macrophages are particularly advantageous cells because, due to the fact that these are resident cells in the skin, they regulate not only local inflammatory reactions but they also regulate the immune responses by their ability to present the antigen and to produce a great number of cytokines which regulate local immunity. These macrophages are also involved in communications with the circulatory system which can, if appropriate, mobilize different cell types (monocytes, neutrophils, eosinophils and T lymphocytes), thus increasing the non-specific and specific defensive power of the tissue under consideration.
The activities of the test products are therefore investigated with respect to human macrophage and keratinocyte cultures which are or are not stimulated by interferon-xcex3+ lipopolysaccharide (non-specific inflammation) or by IL-4 (allergic inflammation). This type of stimulation places the cells in the context of a pro-oxidizing response (generation of NO or superoxide anion free radicals, which can be evaluated by measuring the production of nitrogenous derivatives) and an immuno-inflammatory response (production of cytokines such as TNF-xcex1).
To evaluate the allergic inflammation, the cells are activated by IL-4, which induces the CD23 receptor, and then by IgE-containing immune complexes. In all cases, the cellular supernatants are analysed after the activation.
A viability study is in addition carried out on the cells.
The activity of the components is also confirmed on mixed lympho-epidermal cultures (MLEC).
In the skin, Langherans cells indeed play an essential role in the presence of the antigen and keratinocytes generate factors which are involved in the immune response, thus constituting a cutaneous immune system. MLECs make it possible to determine the immuno-modulatory properties of substances by measuring the lymphocyte proliferation induced by the antigen-presenting allogenic epidermal cells, with or without treatment by the substance.
The results obtained with ginko and xcex2-glucan are summarized in the table below:
Compositions according to the invention contain in particular from 0.001% to 10% w/w of a ginko extract and preferably from 0.05 to 2%; according to one of the embodiments, the concentration of ginkgo extract will be from approximately 0.1 to 0.5% but it will be adjusted by the person skilled in the art.
Concentrations of xcex2-glucan, in particular carboxymethylated xcex2-glucan, which are suitable for the implementation of the invention are within the range from 0.001% to 10% w/total w of the composition.
Other compositions which are particularly suitable for the invention comprise the combination of lactoferrin and drieline, panthenol and green tea extract or panthenol and xcex2-sitosterol. A combination of xcex2-tocopherol (or one of its salts) and a ginkgo extract can also be used according to the invention. Such combinations produce an active hypoallergenic complex which lowers the reactivity threshold of the skin and of the scalp and decreases the magnitude of the possible intolerance or immunoallergic reactions.
The green tea extract is obtained from dry Camellia oleifera leaves and contains, in particular, theophylline, caffeine and theobromine.
Another subject of the invention is a process for the preparation of an active hypoallergenic complex, characterized in that substances belonging to at least one of the groups: anti-free radical, anti-inflammatory and immunomodulatory active principle are selected and in that two substances having complementary activities are then combined so as to potentiate the anti-radical, anti-inflammatory and anti-allergic functions of the combination.
The combination of the substances constituting the active hypoallergenic complex preferably decreases the synthesis or the expression of the neuromediators, such as VIP, PGP 9.5 or CGRP, which are correlated with so-called xe2x80x9csensitivexe2x80x9d or irritable skin.
Another subject of the invention is a method for the cosmetic treatment of sensitive skin comprising the application to the skin of the body or of the face, one or a number of times per day, of active hypoallergenic complexes and/or compositions as defined above.
In particular, the invention relates to a method for the treatment of alopecia which comprises the weekly, twice-weekly, daily or twice-daily application to the scalp of a combination of anti-radical, anti-inflammatory and/or anti-allergic components. The combinations can be in different formulations, such as shampoos or lotions, which can be applied simultaneously, separately or sequentially, optionally with other active principles which are active with respect to alopecia, dandruff conditions and/or seborrhoeic conditions.
Another of the subjects of the invention is the use of a hypoallergenic complex as defined above for the preparation of an immunomodulatory medicament, in particular intended for the treatment of a complaint chosen from atopy, psoriasis, erythema multiforme, xeroder-maztitides, lupus erythematosus, pemphigus, dermatitides, rosacea, acne, eczemas and neurodermatitides.
The hypoallergenic combinations according to the invention will advantageously be formulated within compositions also containing moisturizing agents and/or agents which improve cutaneous penetration, which will promote the activity of the complex according to the invention. Mention may be made, by way of examples, of urea, propylene glycol or oleic acid, the person skilled in the art being capable of using other penetration promoters suited to the type of formulation.
The compositions according to the invention will in addition contain pharmaceutically and/or cosmetologically acceptable excipients known to the person skilled in the art suited to their formulation, in particular in the form of solutions, lotions, creams, shampoos, emulsions, and the like.
Mention may be made, in a non-limiting way, of pigments, dyes, preservatives, texturing agents, thickeners, emulsifiers or fragrances. They can also contain sunscreening agents or blockers or another active principle.
Finally, the hypoallergenic complexes containing the combinations according to the invention can be introduced into compositions containing at least one active principle by the topical route, in particular when this active principle is capable of causing a cutaneous reaction.
Mention may more particularly be made, among such active principles, of retinoids and depigmenting active agents.
Retinoids is understood to mean in particular retinoic acid or tretinoin, retinol, retinaldehydes, their salts and their esters. The alkali metal, ammonium and C2-C30 ammonium salts are typical salts. The sodium, potassium, triethanolammonium and ammonium salts are particularly preferred. The combinations of all the above compounds can be present in the compositions. In addition, the terms xe2x80x9cretinolxe2x80x9d and xe2x80x9cretinoic acidxe2x80x9d must be understood as including the hydrogenated and non-hydrogenated isomers, such as 9-cis-retinol, didehydro-retinol, 13-cis-retinoic acid, 13-trans-retinoic acid and didehydroretinoic acid.
The depigmenting agents comprise, for example, kojic acid, hydroquinone, vitamin C, vitamin C magnesium phosphate, carotenoids, arbutin, and the like.
The following examples are intended to illustrate the invention.